Characterizing a New Human Dendritic Cell Lineage and Its Role in LCH

描述（由申请人提供）：朗格汉斯细胞组织细胞增多症（LCH）是最常见的组织细胞增多症，是一组涉及组织驻留巨噬细胞和树突状细胞的罕见疾病。单系统疾病的患者需要最少的治疗，但即使在这些患者中，也可能有永久性的，主要是矫形后果。在另一个极端，最常见于幼儿，表现为多系统性器官衰竭，在25%的病例中可能是致命的。LCH由朗格汉斯细胞样细胞（也称为LCH细胞）的积累引起。LCH细胞总是与局部细胞因子风暴和大量T细胞浸润相关，导致对包括肺、肝、中枢神经系统和皮肤在内的几个器官的不可逆损伤。LCH研究一直受到与儿童罕见疾病有关的问题的阻碍。个别医生很少看到病例，很难收集到新鲜的材料。两个核心问题仍然没有解决，并阻止适当的治疗：1）LCH细胞的起源是什么？2）LCH是一种真正的肿瘤性疾病还是反应性疾病。回答这些问题将改变我们诊断和治疗这种疾病的方式。目前的范式表明，LCH是由表皮树突状细胞（DC）（也称为“朗格汉斯细胞”（LC））的积累引起的。这一概念是基于观察显示LCH病变被郎格林+细胞浸润及其相关的Birbeck颗粒，这些特征被认为仅限于表皮LC。然而，它一直难以理解如何LC，这是通常限于复层上皮细胞，可以引起这样的多灶性疾病。我们最近发现，在小鼠的大多数非淋巴组织以及人肺和真皮中存在独立于LC的间质性langerin+ DC（图5）。与来源于循环单核细胞的langerin-DCs相反，我们发现langerin+ DCs以Flt 3配体依赖性方式来源于循环DC限制性祖细胞.此外，我们发现受体Flt 3的抑制导致langerin+ DCs的特异性消耗，而langerin-DCs和LC保持不受影响。我们的初步数据还表明，LCH细胞具有类似于间质性langerin+ DCs的表型，并表达高水平的Flt 3。基于这些发现，我们假设LCH是由于间质性langerin+ DCs的积累，而不是LC，并且可以通过前者的失调分子通路来表征。我们还假设受体Flt 3可能代表用于治疗LCH患者的新的治疗靶点。为了解决这一假设，我们在目的1中提出表征在人类健康组织中聚集的langerin+ DCs。在目标2中，我们提出了确定的前体和机制，控制人类langerin+的发展，而在目标3中，我们提出了循环的前体和langerin+ DCs中积累的LCH病变的特点。 公共卫生相关性：郎格罕细胞组织细胞增生症（LCH）的研究一直受到阻碍，难以获得新鲜的材料，并缺乏一个比较的人口，在这里，我们建议进行详细的表征LCH在细胞和分子水平，并使用高度纯化的细胞群体进行比较分析。这些结果应该会导致更好地了解这种疾病，并对这种情况有重要的影响。未来的研究将旨在利用这里获得的数据来建立该疾病的小鼠模型，并将我们的方法扩展到更大的患者队列。

DESCRIPTION (provided by applicant): Langerhans Cell Histiocytosis (LCH) is the most common of histiocytosis, a group of rare diseases that involve tissue-resident macrophages and dendritic cells. Patients with single system disease require minimal treatment, but even in these patients there may be permanent, mainly orthopaedic consequences. At the other extreme and most often in young infants, the presentation is multisystemic with organ failure and can be fatal in 25% of the cases. LCH results from the accumulation of Langerhans cell-like cells also called the LCH cells. LCH cells are always associated with a local cytokine storm and a large T cell infiltrate leading to irreversible damage to several organs that include the lungs, liver, central nervous system and the skin. LCH research has been hampered by problems related to rare diseases of childhood. Individual physicians see few cases and fresh material are hard to collect. The two central questions that remain unresolved and prevent adequate therapy are: 1) what is the origin of the LCH cell and 2) is LCH a true neoplastic or a reactive disorder. Answering these questions would change the way we diagnose and treat the disease. The current paradigm suggests that LCH results from an accumulation of epidermal dendritic cells (DCs) also called "Langerhans cells" (LCs).This concept is based on observations showing that LCH lesions are infiltrated by langerin+ cells and it associated Birbeck granules, features thought to be restricted to epidermal LCs. However, it has been difficult to understand how LCs, which is normally restricted to stratified epithelia, could give rise to such a multi-focal disorder. We recently identified the presence of interstitial langerin+ DCs, independent of LCs, in most non-lymphoid tissue in mice and in human lung and dermis (Fig. 5). In contrast to langerin- DCs that derive from circulating monocytes, we found that langerin+ DCs derive from a circulating DC restricted progenitor in a Flt3 ligand dependent manner. In addition, we found that inhibition of the receptor Flt3 leads to the specific depletion of langerin+ DCs whereas langerin- DCs and LCs remain unaffected. Our preliminary data also suggest that LCH cells have a phenotype that resemble interstitial langerin+ DCs, and express high levels of Flt3. Based on these findings, we hypothesize that LCH is due to an accumulation of interstitial langerin+ DCs, and not LCs, and can be characterized by dysregulated molecular pathways in the former. We also hypothesize that the receptor Flt3 may represent a novel therapeutic target for the treatment of LCH patients. To address this hypothesis we propose in aim 1 to characterize langerin+ DCs that populate in healthy tissues in humans. In aim 2, we propose to identify the precursors and the mechanisms that control the development of human langerin+, while in Aim 3 we propose to characterize the circulating precursors and langerin+ DCs that accumulate in LCH lesions. PUBLIC HEALTH RELEVANCE: Langerhans cell histiocytosis (LCH) research has been handicapped by the difficult access to fresh material and by the lack of a comparative population; here we propose to perform detailed characterization of LCH at the cellular and molecular level and to use highly purified cell populations for comparative analysis. These results should lead to a better understanding of the disease and have important implications for this condition. Future studies will be aimed at utilizing the data acquired here to build mouse models of the disease, and to expand our approach to a larger cohort of patients.